The programmed cell death 1 gene 7209 C>T polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population.

Numerous investigations indicated that the programmed cell death 1 (PDCD1) gene polymorphisms contribute to the development of systemic lupus erythematosus (SLE). However, their association with SLE has been found to be controversial. Therefore, in patients with SLE (n=102) and controls (n=140) we examined the association of six polymorphisms of this gene with susceptibility to SLE in the Polish population. We found that PDCD1 7209 CT or 7209 TT genotype exhibited 3.282-fold increased risk of SLE (95% CI=1.553 - 6.935; p=0.0017). The allele and genotype frequencies of the remaining polymorphisms: 5708 C>T, 6438 G>A, 7146 G>A and 8737 G>A did not exhibit statistical differences between SLE patients and controls. Our results confirmed the association of 7209 C>T polymorphism of PDCD1 gene with SLE that was previously observed in the Taiwanese population.

Contribution of polymorphism in codon 72 of p53 gene to systemic lupus erythematosus in Poland.

The contribution of the p53 Arg72Pro polymorphism in the development of systemic lupus erythematosus (SLE) remains controversial. We investigated the frequency of the p53 Arg72Pro genotype in patients with SLE (n = 155) and in controls (n = 150) in Poland. We found a weak contribution of the Arg/Arg genotype to the morbidity of SLE. Odds ratio (OR) for patients with SLE and p53 Arg/Arg genotype was 1.875 [95% CI = 1.180-2.979], P = 0.0075 and OR of the Arg/Arg and Arg/Pro genotypes was 1.549 [95% CI = 0.752-3.195], P = 0.2328. Since the p53Arg variant supports apoptosis better than the p53Pro variant, our findings can be linked to an increase in the number of apoptotic leucocytes in SLE patients. The distinction between various populations may be because of differences in racial composition and/or exposure to distinct environmental factors that have a different impact on SLE incidence along with the changed Argp53Pro genotype.

MTR 2756 A > G polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by overexpression of cytokines and T cell accessory molecules, which is due to a reduction of DNA regulatory region methylation in T cells. It has been shown that polymorphic variants of genes encoding key enzymes of folate and methionine metabolism may have an effect on DNA methylation. Therefore, in patients with SLE (n = 106) and controls (n = 141) we examined the distribution of polymorphisms of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR). We found that MTR 2756AG (919DG) or GG (919GG) genotype exhibited 2.005-fold increased risk of SLE (95% CI = 1.177-3.416, P = 0.0146). However, MTHFR 677C > T (A222V) and MTHFD1 1958G > A (R653Q) allele and genotype frequencies did not exhibit statistical differences between SLE patients and controls. Since MTR is located on 1q43, our findings confirm the significance of the role of 1q region and the methyl cycle in etiopathogenesis of SLE.

Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium--the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Prevalence of Fc-gammaR chain expression in CD4+ T cells of patients with systemic lupus erythematosus.

OBJECTIVE: To determine the upregulation of transcript and protein levels of the T cell receptor (TCR)/CD3-Fc-gammaR chain in CD4+ T cells of systemic lupus erythematosus (SLE) patients with different clinical disease activity scored on the SLE Disease Activity Index (SLEDAI) scale. METHODS: CD4+ cells were isolated by the positive biomagnetic separation technique. Quantitative analysis of Fc-gammaR cDNA was carried out by using the real-time quantitative polymerase chain reaction (RQ-PCR) SYBR Green I system. Protein levels of Fc-gammaR in CD4+ T cells were determined by Western blotting analysis. RESULTS: We observed significantly higher transcript and protein levels of the Fc-gammaR chain in CD4+ T cells of SLE patients (n = 45) than in healthy individuals (n = 26). The increase in Fc-gammaR expression was observed in 97.8% of SLE patients. Spearman statistical analysis suggests that the protein level of Fc-gammaR in CD4+ T cells may correlate with SLE activity scored by the SLEDAI scale (R = 0.556, p < 0.00006, respectively). CONCLUSION: The high prevalence of the Fc-gammaR chain in CD4+ T cells of SLE patients may indicate an important role for this molecule in the pathogenesis of SLE.

[Variety of initial symptoms in patients with Wegener's granulomatosis]. / Róznorodnosc objawów poczatkowych u chorych z ziaminiakiem Wegenera.

Wegener's granulomatosis is a necrotizing vasculitis with heterogenous initial symptoms what may still cause diagnostic problems. We present analysis of initial symptoms of 14 patients with Wegener's granulomatosis to evaluate their value in early diagnosis. Involvement of kidneys as well as upper and lower airways may suggest the diagnosis. Acute onset with intensified general symptoms may provoke more intensive diagnostic procedures and the diagnosis can be established earlier. In patients with non-acute onset the diagnosis may be delay, in some cases a few years after the first symptoms.

Lessons from the "Euro-Lupus Cohort".

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVE: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. METHODS: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. RESULTS: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. CONCLUSIONS: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis.

The use of intravenous immunoglobulin (IVIg) has been reported as an immunomodulating agent in several autoimmune diseases, including systemic lupus erythematosus (SLE). Herein we report a SLE patient with severe clinical presentation that included pericarditis, pleural effusion, nephrotic range proteinuria, leukopenia, and lymphopenia. The patient received one course of high-dose IVIg (2.8 g/kg body weight), and within a week of post-IVIg therapy, her condition significantly improved. One-month post-IVIg there were decreased proteinuria, elevated leukocytes and lymphocytes count, decrease in antinuclear and anti-dsDNA antibodies, and disappearance of pericarditis and pleuritis. This case demonstrates the efficacy of IVIg in severe SLE with various clinical manifestations.

Evaluation of cerebrospinal fluid for the presense of anticardiolipin antibodies (aCL) in NP-SLE patients.

Many neurological or psychiatric manifestations of SLE (NP-SLE) are related to the presence of anticardiolipin antibodies (aCL) in the patient's sera. The aim of this study was to evaluate the presence of aCL in cerebrospinal fluid (CSF) in SLE patients with NP features. Fifteen SLE patients were studied, all with NP features. CSF was evaluated for intrathecal IgG synthesis, oligoclonal IgG, and blood-brain barrier impairment. Sera and CSF were tested by ELISA for the presence of aCL-IgG and aCL-IgM with and without beta2 glycoprotein (beta2 GPI) cofactor. CSF and sera of 50 low back pain patients served as controls. Six patients were aCL(+) and nine aCL(-). In all patients the general CSF examination was normal. In all patients the value of indices of intrathecal IgG synthesis were normal but oligoclonal protein was present in the CSF of three patients. In none of the patients was the blood-brain barrier impaired. Neither aCL-IgG nor aCL-IgM was detected in the CSF of any NP-SLE patient. Mean levels of aCL in patients without cofactor beta2 GPI and with cofactor were as follows: for IgG class 0.005 and 0.057 OD (negative); for IgM class 0.004 and 0.024 OD (negative). We could not detect aCL in the CSF of patients with NP-SLE, even if sera were positive for aCL.

High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism.

Recent data suggest that IL-15 plays an important role in the pathogenesis of rheumatoid arthritis. In the present study, we hypothesized that elevated in the joints of rheumatoid arthritis, but not osteoarthritis, patients, IL-15 may exert its proinflammatory properties via the induction of IL-17, a cytokine known to stimulate synoviocytes to release several mediators of inflammation including IL-6, IL-8, GM-CSF and PGE2. To test this hypothesis, we first measured the levels of IL-17 and IL-15 using specific ELISA and found that synovial fluids of patients with rheumatoid arthritis, but not with osteoarthritis, contain high levels of these cytokines. A strong correlation between IL-15 and IL-17 levels in synovial fluids was observed. Among tested factors, LPS and TNF-alpha failed, IL-15 and IL-2 were equipotent, and PMA + ionomycin was far more efficient in the induction of IL-17 secretion by PBMCs isolated from healthy blood donors. Interestingly, synovial fluid cells, in contrast to PBMCs isolated from patients with rheumatoid arthritis, but not osteoarthritis, respond to PMA + ionomycin with much lower, comparable to IL-15-triggered IL-17 secretion. Moreover, PMA + ionomycin-triggered IL-17 secretion is completely or partially blocked in the presence of low doses of cyclosporin A or high doses of methylprednisolone, respectively. IL-15-triggered IL-17 secretion by PBMCs was completely inhibited by these drugs. Thus, our results suggest for the first time that IL-15 may represent a physiological trigger that via cyclosporin A and steroid sensitive pathways leads to the overproduction of IL-17 in the joints of rheumatoid arthritis patients.

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

Extrapulmonary location of sarcoidosis.

Two cases of sarcoidosis located outside the lungs are reported. In both cases the symptoms of the sicca syndrome were in the foreground. In the first case other clinical manifestations included mediastinal and retroperitoneal lymphadenopathy, and lacrimal gland impairment. In the other case the symptoms of the sicca syndrome were associated with polyneuropathy and maculopapular skin rash. The diagnosis of sarcoidosis was confirmed by histological examination of a biopsy specimen of lower lip mucosa in the first case, and biopsy of skin lesion in the second case. Abnormal results of laboratory tests included only raised erythrocyte sedimentation rate, in both cases and presence of circulating immune complexes in one case. Serological tests failed to demonstrate the presence of rheumatoid factor, antinuclear and anti-ds DNA antibodies. No decrease was observed also in the haemolytic activity of the complement, and cryoglobulins were absent. Regression of clinical signs was obtained in both cases after treatment with glucocorticosteroids.

Polymyositis-dermatomyositis--a 25-year follow-up of 50 patients (analysis of clinical symptoms and signs and results of laboratory tests).

Clinical symptoms and signs and the frequency of abnormalities in the results of enzymatic, electromyographic, histological and serological tests were analysed in 50 patients, including 17 with polymyositis (PM) and 33 with dermatomyositis (DM), groups I and II according to Bohan's classification and followed-up for 25 years. Weakness of the proximal muscles of the extremities was present in both groups in all patients and in a high proportion of cases weakness involved also the distal muscles. Dysphagia was more frequent in DM patients (54.5%) than in PM (17.6%). In DM erythema and facial oedema as well as Gottron's sign were observed more frequently. In 11.8% of PM patients and 15.1% of DM patients deposition of calcium salts in subcutaneous tissue developed. Signs of vasculitis were found in 39.4% of DM cases and 17.6% of PM cases. In one-third of PM and in only 3 DM cases pitting oedema of the distal parts of the extremities was noted. Cardiovascular changes were disclosed in 82.3% of PM and 69.7% of DM patients. On the other hand, radiological signs of interstitial pulmonary fibrosis were noted more frequently in DM (36%) than in PM (23%). Increased serum activity of CPK, AspAT and ALAT was present with similar frequency in both groups from 71% to 81% of cases. EMG showed evidence of primary muscular changes in all PM patients and 69.6% of DM patients. Histological examination confirmed the diagnosis in the studied patients. Antinuclear antibodies were found relatively rarely, from 2% to 24% of PM/DM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Polymyositis-dermatomyositis:25 years of follow-up of 50 patients disease course, treatment, prognostic factors.

Therapeutic results were analysed in 50 patients, including 17 with polymyositis (PM) and 30 with dermatomyositis (DM). All patients were treated with prednisone (Encorton, Polfa) and 47% of patients with PM and 73% with DM required combined treatment with prednisone and cytostatic agents, mostly with cyclophosphamide (Endoxan G.D.R.). Long-term treatment monitored with the clinical status led to remissions persisting after treatment discontinuation in 17.6% of PM patients and 24.2% of DM patients. In 64.7% of PM patients and 57.6% of DM patients regression of the clinical signs of the disease was achieved but these patients required further treatment. No information was obtained on 5 cases. Four DM patients died. The cumulative 17-year survival rate of PM patients was 100%, and that of DM patients was 78.8% . In 45 follow-up cases, the mortality was 8.9%. Side effects of the combined treatment included most frequently mucosal candidiasis (22.2%), transient leucopenia (14.8%) and recurrent respiratory tract infections (11.1%). In 5 cases liver biopsy was done and histological examination disclosed moderate fatty, glycogen and vacuolar degeneration of the hepatocytes. The statistical analysis of prognostic factors such as the diagnosis of PM or DM, sex, age at disease onset, disease duration till diagnosis establishing and beginning of treatment, fever, dysphagia, circulatory and respiratory changes, leucocytosis nad ESR at the beginning of the disease showed that sex (female), older age at disease onset and respiratory system changes may be accepted as poor prognosis factors.